Medicine and Health Sciences Commons^™

Whsc1l1 Regulates Estrogen Receptor Activity In Sum44 Breast Cancer Cells, Jonathan Curtis Irish

Wayne State University Dissertations

Breast cancer is the most common cancer and the second leading

cause of cancer death in women. While ER-positive breast cancer subtypes are initially

well-managed by targeted therapies targeting estrogen signaling, many women are

suffering from recurrence of a more aggressive, hormone insensitive cancer 5 or more years after initial remission. Late recurrence of hormone resistant breast cancer in patients

who were previously successfully treated with anti-estrogen therapies worsens

overall long-term outcomes, and specific oncogenic mutations may be driving late recurring aggressive disease in these patients. More complete characterization of the oncogenome of

a tumor may allow for the possibility …

Adipocyte-Induced Inflammation In Prostate Tumor Progression In Bone: Role Of Cxcr2 And Osteopontin, Aimalie Lynnette Hardaway

Wayne State University Dissertations

Abstract

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men. Evidence suggests that age and obesity, conditions associated with adipocyte accumulation in the bone marrow, are linked to increased risk of developing PCa and progressing to metastatic disease. Studies presented in this dissertation were based on the hypothesis that metastatic progression in bone is a result of a cooperative effort between bone marrow adipocytes, macrophages, osteoclasts, and PCa cells. We specifically focused on two adipocyte-supplied chemokines, CXCL1 and CXCL2, and bone marrow macrophage-secreted osteopontin as key drivers of pro-inflammatory environment in the bone marrow and important …

What Impacts Life Satisfaction Of Aging Adults Following Stressful Life Events?: An Examination Of The Buffering Effect Of Personal Resources, Cassandra Barragan

Wayne State University Dissertations

Purpose: Existing research has shown that elders experience changes in their life satisfaction following stressful life events. There is an abundance of literature supporting the predictive nature of not only stressful life events on life satisfaction, but social support, autonomy, and financial security. What the literature is lacking, is examination of the buffering effect of social support, autonomy, and financial security on the relationship between stressful life events and life satisfaction. This study hypothesizes that increases in social support, autonomy, and financial security will buffer the impact of SLEs for elders and thus, they will experience increases in their life …

The Therapeutic Targeting Of Folate Receptor Alpha Positive Tumors Via Folate Receptor Selective Novel 5- And 6- Substituted Pyrrolo [2,3-D]Pyrimidine Antifolates", Shermaine Kimberly Mitchell-Ryan

Wayne State University Dissertations

Ovarian Cancer is the fifth leading cause of cancer-related death of women in the United States. Epithelial Ovarian Cancer (EOC) constitutes 85-90% of malignancies within the ovary, with an alarming majority of these cases diagnosed at advanced stage. While most patients are initially highly responsive to the current treatment standard, there is a very high probability that they will recur with a drug resistant fatal disease. Currently there is no validated comprehensive model of disease progression for ovarian cancer, although tremendous progress has been made in understanding the origin of this disease and a putative precursor lesion has been identified …

Engagement In Activities And Cognitive Functioning Among Older Adults In The Health And Retirement Study, Pamela Emily May

Wayne State University Dissertations

The goal of this dissertation is to examine the effect of cognitive and social activities on cognitive performance and health conditions in a national sample of older adults from the Health and Retirement Study (HRS). This dissertation first aimed to identify longitudinal relations between activity frequency and cognitive functioning. Two hypotheses were tested, baseline activity frequency predicts change in cognitive functioning over time, and baseline cognitive performance predicts change in activity frequency over time. The dissertation’s second aim was to identify links between activity frequency and cognitive trajectories. The third aim was to identify longitudinal relations between activity frequency and …

The Experiences Of Black American Older Adults Managing Pain: A Nursing Ethnography, Sheria Grice Robinson

Wayne State University Dissertations

Introduction: Pain can negatively affect quality of life for Black elders. They are less likely to report pain concerns and have voiced pain needs adequately met. To better understand the pain management experiences and concerns of Black elders, an ethnographic study was completed within an urban, low-income, elder housing facility. Methods: 106 participants completed a questionnaire comprised of a demographic tool, the PROMIS Global Health Scale (PROMIS), the Brief Pain Inventory (BPI), and the Psychological Stress Measure (PSM-9). Additionally, participant observation, informal interviews, and 20 formal recorded interviews with individuals identified as having pain were completed. Qualitative and frequency analysis …

African American Grandparents Residing In A Nursing Facility: Perceptions Of Influence With Their Grandchildren, Family, And Community, Monica Bester

Wayne State University Theses

African American older adults have historically been identified as vital members of the African American family and community (Hill, 1972; Cox, 2002; Waites, 2008). Unfortunately, research has shown an increasing number of older African Americans are being admitted into nursing facilities (Paul, 2004; Feng et al., 2011). Between the years of 1998-2008, it was projected African Americans living in nursing homes increased by 10.8% (Feng et al., 2011).

This study explores the intergenerational relationships of older African American adults with their grandchildren, family, and community through the lens of Intergenerational Family Systems Theory. By viewing this qualitative study through the …

Photodynamic Therapy As An Effective Therapeutic Approach In Mame Models Of Triple Negative And Inflammatory Breast Cancers, Neha Aggarwal

Wayne State University Dissertations

Introduction: Photodynamic therapy (PDT) is a minimally invasive, FDA approved therapy for

treatment of several indications including endobronchial and esophageal cancers that are

accessible to light. Triple negative breast cancer (TNBC) and inflammatory breast cancer (IBC)

are aggressive and lethal subtypes of breast cancer that spread to chest wall and dermal

lymphatics, respectively, sites that would be accessible to light. Both TNBC and IBC patients

have a relatively poor survival rate due to lack of targeted therapies. Use of PDT is

underexplored for breast cancers but has been proposed for treatment of subtypes for which a

targeted therapy is unavailable. …

Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer, Julie Marie Madden

Wayne State University Dissertations

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of GEF, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment …

Pathway Profiling Of Replicative And Induced Senescence, Maggie Purcell

Wayne State University Dissertations

Senescence is a permanent withdrawal from cell cycle that occurs naturally in cells in response to the shortening of telomeres. This natural "clock" serves to limit the number of cell divisions and therefore protects the cell from potentially carcinogenic mutations. However, senescence also occurs in response to external stresses to the cell, which is known as induced senescence. This study compares the mechanisms of natural senescence, a response to the shortening of telomeres during replication, with induced senescence by using various drugs to induce senescence: 5-aza-2-deoxycytidine (a demethylating agent), Adriamycin (a chemotherapeutic drug), and H2O2 (an agent causing oxidative stress). …

Cervical Remodeling/Ripening At Term And Preterm Delivery: The Same Mechanism Initiated By Different Mediators And Different Effector Cells, Juan Miguel Gonzalez Velez

Wayne State University Dissertations

Premature cervical remodeling/ripening is believed to contribute to preterm delivery (PTD), the leading cause of perinatal morbidity and mortality. Despite considerable research, the causes of term and PTD remain unclear, and there is no effective treatment for PTD. We tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied cervical remodeling at term.

We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS)and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophage infiltration and increased serum C3adesArg and C5adesArg …

Dendrimer Based Nanotherapeutics For Ocular Drug Delivery, Siva Pramodh Kambhampati

Wayne State University Dissertations

PAMAM dendrimers are a class of well-defined, hyperbranched polymeric nanocarriers that are being investigated for ocular drug and gene delivery. Their favorable properties such as small size, multivalency and water solubility can provide significant opportunities for many biologically unstable drugs and allows potentially favorable ocular biodistribution. This work exploits hydroxyl terminated dendrimers (G4-OH) as drug/gene delivery vehicles that can target retinal microglia and pigment epithelium via systemic delivery with improved efficacy at much lower concentrations without any side effects.

Two different drugs Triamcinolone acetonide (TA) and N-Acetyl Cysteine (NAC) conjugated to G4-OH dendrimers showed tailorable sustained release in physiological relevant …

The Role Of Pdgf C And Its Splice Variant In Breast Cancer, Alyssa Bottrell

Wayne State University Dissertations

The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C …

Molecular Studies On The Anti-Tumor Effects Of Metal-Based Complexes: Involvement Of The Ubiquitin-Proteasome And Apoptotic Pathways, Sara M. Schmitt

Wayne State University Dissertations

The ubiquitin-proteasome pathway is crucial to normal cellular function, and as such, has been extensively investigated as a potential target for cancer therapeutics. Many compounds have been tested for their proteasome inhibitory ability, including various small peptide aldehydes, and, following the success of cisplatin, several metal-containing complexes. The efficacy of these compounds in preclinical studies ultimately resulted in the development and approval of the first-in-class proteasome inhibitor bortezomib, the use of which, unfortunately, has been hindered by toxicity and resistance. These limitations have led to a massive push toward designing and developing new, less toxic proteasome inhibitors for clinical use. …

Tmprss2-Erg Regulation Of Androgen Biosynthetic Enzyme Expression, Dht Synthesis, And Androgen Receptor Activation In Prostate Cancer, Katelyn Ann Powell

Wayne State University Dissertations

Intratumoral androgen synthesis in prostate cancer (PCa) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus, contributing to CRPC in a castrated environment. Although intratumoral androgen synthesis is thought to contribute to the development and progression of CRPC, currently little is known regarding the regulation of androgen biosynthetic enzyme gene expression in PCa. The TMPRSS2-ERG transcription factor has been shown to be present in primary PCa tumors as well as CRPC tumors. The hypothesis was investigated that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene …

Physical Activity And Exercise During Adolescence And Young Adulthood Can Act As Preventative Measures Against The Development Of Osteoporosis In Elderly People, Christine C. Center

Honors College Theses

Osteoporosis, “the silent killer,” is responsible for 8.9 million annual fractures. Although not bound to these factors, osteoporosis typically targets females that are post-menopausal and have a family history of the disease. Osteoporosis is caused by a decrease in bone mass density. Physical activity and exercise and often spoken about when the topic of osteoporosis is discussed because of the impact they have on maintaining bone mass density in an effort to delay osteoporosis. This paper first provides an overview of osteoporosis, explanation of methods of diagnosing osteoporosis, risk factors, complications and treatment for osteoporosis. Topics covered include, bone mass …

Characterization Of High-Voltage-Activated Calcium Channels In Retinal Bipolar Cells, Qi Lu

Wayne State University Dissertations

Retinal bipolar cells, conveying visual information from photoreceptors to ganglion cells, segregate visual information into multiple parallel pathways through their diversified cell types and physiological properties. Voltage-gated Ca²⁺ channels could be particularly important underlying the diversified physiological properties of different BCs. In this dissertation, I investigated the high-voltage-activated (HVA) calcium current in retinal bipolar cells in mice. In the first part of my dissertation, I characterized multiple bipolar cell-expressing GFP and/or Cre transgenic mouse lines. In the second part of my dissertation, by performing whole-cell patch-clamp recordings, I examined the electrophysiological properties of HVA calcium currents among CBCs and …

Impact Of Cryoablation On Tumor Immunity, Jesse Veenstra

Wayne State University Dissertations

Background and Objectives: Percutaneous cryoablation is a minimally invasive procedure for tumor debulking, which has the potential to initiate or amplify tumor immunity through the release of tumor-associated antigens and endogenous danger signals. However, enhanced immunity is rarely observed in treated patients, suggesting the need for mechanistic analysis. The goal is to determine how cryoablation affects tumor specific immunity and if the response can be improved through exogenous TLR9 stimulation.

Methodology: We evaluated anti-Her2/neu immunity following cryoablation in wt BALB/c and tolerant NeuT mice inoculated with neu or Her2 expressing mammary tumors TUBO and D2F2/E2 respectively. Mice were treated with …

Expression And Regulation Of Map Kinase Phosphatases 1 And 2 In Breast Cancer Tamoxifen Sensitivity, Kelly Haagenson

Wayne State University Dissertations

ABSTRACT

EXPRESSION AND REGULATION OF MAP KINASE PHOSPHATASES 1 and 2 IN BREAST CANCER TAMOXIFEN SENSITIVITY

by

KELLY K. HAAGENSON

May 2013

Advisor: Dr. Malathy Shekhar

Co-Advisor: Dr. Gen Sheng Wu

Major: Cancer Biology

Degree: Doctor of Philosophy

The deregulation of cell signaling is a very important component in the development and progression of cancer. One group of signaling molecules that has been implicated in these processes is the Mitogen-Activated Protein Kinase (MAPK) family which consists of three major branches in mammalian cells: ERK, JNK and p38. The activity of these kinases has wide-ranging effects within the cell and must …

Multi-Modality Assessment Of Language Function, Erik Carmen Brown

Wayne State University Dissertations

The work presented as part of this dissertation represents a multi-modality study of language structure and function. The primary functional modality employed is task-related electrocorticography (ECoG). This is complemented by discussion and evaluation of previously published functional magnetic resonance imaging (fMRI) data. Language-related structure is explored using diffusion-weighted magnetic resonance imaging in conjunction with ECoG data. The scientific questions pursued are broad and include reevaluation of previously proposed theories.

We start by taking the first steps in validating our naming-related ECoG approach by comparing our results from a small cohort of patients to the clinical gold-standard technique of electrical brain …

Linking Environmental Toxicant Exposure To Diabetes Susceptibility, Jannifer Beth Tyrrell

Wayne State University Dissertations

An important and unresolved question in the environmental health field is whether exposure to common environmental toxicants, such as dioxin and heavy metals like Pb, increase the risk of developing diabetes, especially in combination with other common metabolic stressors such as obesity.

Previous studies suggested that dioxin exposure increased peripheral insulin resistance but did not appear to cause fasting hyperglycemia or elevated hepatic glucose output. In concordance with those findings we observed that dioxin treatment caused a strong suppression of the expression of the key hepatic gluconeogenic genes PEPCK and G6Pase. However, this suppression was not solely mediated by the …

Advanced Augmented Reality Telestration Techniques With Applications In Laparoscopic And Robotic Surgery, Stephen Dworzecki

Wayne State University Dissertations

The art of teaching laparoscopic or robotic surgery currently has a primary reliance on an expert surgeon tutoring a student during a live surgery. During these operations, surgeons are viewing the inside of the body through a manipulatable camera. Due to the viewpoint translation and narrow field of view, these techniques have a substantial learning curve in order to gain the mastery necessary to operate safely. In addition to moving and rotating the camera, the surgeon must also manipulate tools inserted into the body. These tools are only visible on camera, and pass through a pivot point on the body …

Analysis Of The Structure And Function Of A Timp-1/Cd63 Complex And Its Relationship To An Mt1-Mmp/Cd63 Complex, Richard B. Warner

Wayne State University Dissertations

The relationship of the extra-cellular matrix (ECM) and secreted proteins to intra-cellular functions has an important impact on disease progression. The tissue inhibitors of metalloproteinases (TIMPs), of which there are four, are known for their broad metalloprotease inhibitory abilities. TIMP-1 has been widely studied as an inhibitor of matrix metalloproteinases (MMPs) and therefore as a molecule that prevents ECM degradation and proteolytic cleavage of extra-cellular molecules, processes thought to be critical for tumor invasion and metastasis. However, TIMP-1 has shown in the clinic to have increased expression in cases of disease progression; especially, it is associated with poor prognosis in …

The Bca2 And Ampk Paradigm: Unraveling The Cancer Connection, Daniela (Buac) Ventro

Wayne State University Dissertations

THE BCA2 & AMPK PARADIGM: UNRAVELING THE CANCER CONNECTION

By

DANIELA (BUAC) VENTRO

December 2013

Advisor: Dr. Q Ping Dou and Angelika M. Burger (deceased)

Major: Cancer Biology

Degree: Doctor of Philosophy

Adenosine monophosphate-activated kinase (AMPK), a master regulator of cellular energy homeostasis, has emerged as a promising molecular target in the prevention of breast cancer, and phase II and III clinical trials using the FDA-approved, AMPK activating, anti-diabetic drug metformin are promising in this regard, but the question of why metformin is protective for some women but not others still remains. Breast Cancer Associated Gene 2 (BCA2/Rabring7/RNF115), a novel …

White Matter Integrity And Age Related Differences In Reaction Time Components, Yiqin Yang

Wayne State University Dissertations

Reduced speed in information processing is a well-documented phenomenon associated with advanced aging. Age-related deterioration in white matter integrity might play a role in age-related increase in reaction time (RT). However, the association between microstructural differences in particular white matter regions or tracts with RT is unclear. Decomposing RT into parts might be a better way to understand the relationship due to multiple processes involved in RT. In a lifespan sample of 90 healthy normotensive participants, this study examined the association between RT components derived from the Ratcliff diffusion model with age related difference in DTI indices of a wide …

Prenatal Genetic Diagnosis Using Transcervically Derived And Immunomagnetically Isolated Trophoblast Cells, Swati Bajpayee

Honors College Theses

Trophoblast cells migrate from the placenta into the endocervical canal early in the first trimester and can be collected non-invasively by transcervical sampling (TCS), potentially providing fetal DNA for prenatal genetic diagnosis. Experiments were conducted to separate fetal cells from maternal cells within the TCS specimens and use the fetal cells to perform genetic analysis. Trophoblast cells were efficiently isolated from TCS specimens during weeks 5-18 of gestation using HLA-G antibody coupled to magnetic nanoparticles. Immunofluorescence microscopy revealed that 99% of isolated cells expressed the chorionic gonadotropin β subunit (β-CG), while the non-bound cell fraction expressed none. Immunomagnetically isolated cells …

Patients' And Caregivers' Inside Perspectives: Living With A Left-Ventricular Assist Device As Destination Therapy, Linda Marcuccilli

Wayne State University Dissertations

Left-ventricular assist devices (LVADs) have improved the quality of life for many patients with advanced heart failure. Past research focused on technology issues and survival rates, but patients' and caregivers' perspectives of living with an LVAD as a destination therapy (e.g., permanent alternative to transplant) was not explored. Roy's adaptation model provided a framework to guide an understanding of how participants adjusted and accepted living with destination therapy. A hermeneutic-phenomenology as described by van Manen was used to explore and describe the essence of destination therapy from patients' and caregivers' perspectives in order to understand the meaning of this experience. …

A Role For Reactive Oxygen Species In Photodynamic Therapy, Michael Price

Wayne State University Dissertations

Photodynamic therapy (PDT) is based on the ability of certain photosensitizing agents to selectively localize in neoplastic cells and their vasculature. Subsequent irradiation at a wavelength corresponding to a photosensitizer absorbance band excites the photosensitizer molecules, leading to energy transfer reactions and fluorescence. It was initially concluded that the phototoxic effect occurred when energy from the excited state of the photosensitizer was transferred to dissolved oxygen to form singlet oxygen. This product has a very brief half-life and will cause cellular damage only in the immediate vicinity of its formation. But an excited-state photosensitizer can also interact with oxygen to …

The Proton-Coupled Folate Transporter: Biology And Therapeutic Applications To Cancer, Sita Desmoulin

Wayne State University Dissertations

Folates are essential cofactors of tumor cell proliferation and survival required for nucleotide biosynthesis and amino acid metabolism. In cancer therapy, inhibition of folate-dependent metabolic pathways has been achieved through the use of antifolates. Unfortunately, the efficacy of many clinically approved antifolates is limited by a lack of tumor selectivity. Facilitative transport of folates into mammalian cells is achieved by the reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). As PCFT is a folate-proton symporter with an acidic pH optimum, PCFT may provide a mechanism for targeting cytotoxic antifolates to tumors, based on their acidic microenvironments. To establish the …

Modulation Of Anti-Tumor Immune Response By Tgf-Β-Inducible Early Gene 1 (Tieg1), Andi Cani

Wayne State University Theses

Cancer immunotherapy has had limited clinical efficacy partly because regulatory T cells (Treg) suppress the immune response to tumor-associated antigens. Inducible regulatory T cells (iTreg), which are converted from naïve CD4 T cells by TGF-β, an abundant cytokine in the tumor microenvironment, may contribute to this immune suppression. Induction of Foxp3 by TGF-β is mediated by the transcription factor TIEG1 and abrogation of this protein prevents Foxp3 expression. We are testing the hypothesis that blockade of TIEG1 to prevent iTreg conversion will enhance immune response in DNA vaccination to the tumor associated antigen Her-2. Wild type and TIEG1 knockout mice …